1
Q
What does parenteral mean?
A
par(a) = beside/outside enetral = intestine
2
Q
what is parenteral administration?
A
- par(a) = beside
- enteral = intestine
- therefore any route that bypasses the intestine
3
Q
What is the BP definition of parenteral administration?
A
sterile preparations for administration by injection, implantation, infusion into humans or animals
4
Q
According to the BP, parenteral preparations must be sterile. What are two approaches to sterilisation and what do they need to ensure and avoid?
A
- aseptic preparation
- terminal sterilisation
- need to ensure sterility
- need to avoid contaminants
5
Q
Why is parenteral administration useful? (5)
A
- can be used for drugs w low stability in GIT
- local administration - higher concs e.g. intra-ocular
- GIT may not be available
- rapid onset of action; emergencies (no additional step like with caps and tabs)
- achieving prolonged release (implants, IM)
6
Q
What types of drugs is parenteral administration useful for? (2)
A
- those with low stability in the GI tract
- those which need prolonged release (implants, IM)
7
Q
In what patient-related situations is parenteral administration useful?
A
- emergencies: due to rapid onset of action
- unconscious/dysphagia: makes GIT unavailable as patient cannot swallow
8
Q
What are the 3 main routes of parenteral administration?
A
- intravenous (25 degrees)
- subcutaneous (45 degrees)
- intramuscular (90 degrees, deepest needle)
9
Q
whats IV route of parenteral admin: administered into and used for?
A
veins inside dermin
used for allergy tests etc…
10
Q
where is IM injected into?
A
deepest of the injections
90 degree angle
tissue layer under dermis
11
Q
Apart from the 3 main routes, what are other routes of parenteral administration?
A
- intra-arterial
- intra-articular (joints)
- intra-synovial
- intracameral
- intracardiac
….
…
12
Q
describe IV injection- how much and where admin?
A
Single dose
Continuous infusion: therefore control rate
Peripheral or central vein
13
Q
IV volume administered- when is small vol used and when large?
A
Small (<10 mL)
Emergency
Large (>500 mL)
Fluid replacement
Nutrition
14
Q
types of IV formulation examples
A
Aqueous:
- Solutions
- Emulsions
- Nanosuspensions not normal as bigger particles can embolise in small capillaries
15
Q
routes of Intravenous administration? (2)
A
Peripheral vein
• Forearm/elbow
• Back of hand
Central vein
• Frequent access required
• Limited peripheral access
16
Q
examples of intravenous administration
A
- Antibiotics (long term)
- Parenteral nutrition
- Chemotherapy
17
Q
IV soln may be irritating. how can you avoid damaging peripheral veins?
A
can dilute, prevent pain and irritation
18
Q
advantages of IV administration
A
- 100% bioav
- rapid onset of action
- rapid dilution in blood circ
- useful if drug too irritating for SC/IM
- self admin possible- e.g. PCA devices
- useful is no other routes available
19
Q
disadvantages of parenteral administration (all)
A
- Invasive, inconvenient, restrictive
- Training required
- Strict sterility requirements
- Higher production costs
- Aseptic techniques required
- Risk for conversion errors
- Can be/is perceived as painful
- Management of waste (sharps)
- Formulation can be challenging
- Difficulty to self-administer
20
Q
Subcutaneous administration: injection- where?
A
Fatty tissue under dermis
Upper arm
Anterior thigh
Lower abdomen
Proximity of capillaries
tissues-> caps -> blood circ -> lymphatic circs
21
Q
Subcutaneous administration: volume- how much and mixed with what?
A
Small (1-2 mL) Large with: Divided doses Hypodermoclysis SC infusion Slow rate Palliative/hydration To be mixed with hyaluronidase: break down connective tissue
22
Q
Subcutaneous administration types of formulation?
A
Aqueous solutions
Aqueous suspension
Oily solutions
Oily suspensions
23
Q
Subcutaneous administration formulation and liposolubility impact on? (2)
A
Diffusion rate
Onset of action
24
Q
use of hyaluronidase in SC preps?
benefit
A
Hyalase
mix w drug, : break down connective tissue
allow admin of larger volumes?
25
2 examples of large volume SC?
Trastuzumab (Herceptin®)
- 5 mL over 2-5 minutes
Rituximab (MabThera® SC)
- 11.7 mL over 5 minutes
26
SC 3 advantages?
Considered more patient friendly than IV
Patients can be taught to self inject
Formulations can be made as suspensions
27
specific SC disadvantages?
same as all parenterals PLUS:
- <100% bioavailability
- Response not always predictable
- Some enzymatic activity (e.g. peptidases)
28
whys response not always predictable in SC admin? what 3 factors influence it?
Impact of changes in :
• Blood supply
• Temperature
• Site of injection
29
2 disadvantages specific to IM?
same as all parenterals PLUS:
- Risk of embolism !!!
- Risk of extravasation
30
IM injection- where administered?
Skeletal muscle - Below SC tissue
Far from
• nerves
• blood vessels
Upper arm - Deltoid
Thigh - Vastus lateralis
Buttock - Gluteal
31
Intramuscular administration what vols administered and where?
Small (< 4 mL)
Up to 10 mL in divided doses
• Gluteus in adults
• Thigh in younger patients
32
types of IM formulation?
* Aqueous solutions
* Aqueous suspension
* Oily solutions
* Oily suspensions
* Oily emulsions
Impact of formulation and liposolubility on
• Diffusion rate
• Onset of action
33
4 examples of IM administation?
COVID-19 (and other) vaccines
Haloperidol decanoate
Penicillin G benzathine
EpiPen®
34
IM advantages?
```
Considered more patient friendly than IV
Rapid onset of action possible
Variety of formulations available
Alternative to SC for irritant drugs
Useful if no other routes possible
Possible controlled release
Better than SC for larger volumes
```
35
IM specific disadvantages? (2)
Difficulty to self-administer
| Impact of blood supply on absorption
36
what else to consider specifically with IM admin?
With muscle: think about exercise and affect on blood supply
37
5 categories to consider in formulations?
```
sterility- avoids natural mech of defense+ phys barriers
excipients
containers
endotoxins: bacterial byproduct
particulates
```
38
what must excipients be like in these formulations?
Can play different roles but must be compatible and nontoxic
39
what must containers be like in these formulations?
Can be made of glass or plastic, ideally clear
Should protect the product from contamination during storage
Should be tamper-evident so can see if anyhting gone out/in
40
what to consider regarding endotoxins in these formulations?
Lipopolysaccharides (LPS)
Endotoxins cause fever and can cause shock. must control levels carefully
See Sterile products for depyrogenation
41
what to consider regarding particulates in these formulations?
Free of visible particles
| Limited sub-visible particle content
42
what will the BP provide information on?
* Limits for sub-visible particles
| * Limits for bacterial endotoxin units (pyrogens)
43
in BP, what will Limits for sub-visible particles depend on? and 2 exemptions?
route of administration: IV stricter limits than other two
Usually higher for SC or IM
Exemptions:
o Radiopharmaceuticals
o Products to be used with a final filter (final product must meet requirement)
44
in BP, what will Limits for bacterial endotoxin units (pyrogens) depend on?
route of administration and maximum dose recommended
45
what 6 features of excipients to consider?
* Isotonicity
* pH
* Solubility
* Drug stability
* Formulation shelf-life
* Preservation
46
Parenteral formulations: 3 types of form?
solutions
emulsions
suspensions
47
Parenteral formulations: solutions used what do they req? (4)
```
Water for injections
Co-solvents
Ethanol
Glycerol
Propylene glycol
Solubilising agents
Surfactants
Cyclodextrins
Suitable oil
```
48
Parenteral formulations: emulsion used what do they req? (3)
```
w/o or o/w. contain:
Water for injections
Emulsifiers
Lecithin
Sorbitan fatty acid ester
Suitable oils
Arachis oil
Sesame oil
Soybean oil
```
49
Parenteral formulations: suspensions used what do they req?
can be aqueous or oily too
- Water for injection
- Suspending agents
- Wetting agents. Surfactants e.g polysorbate
- Suitable oils
50
role of suspending agents in emulsions and example?
Increase viscosity and stability and change drug release profile
Methylcellulose (IM)
51
what are suspensions best for?
best for SC and IM.
risk of embolism with IV.
but if have colloidal susp for nanomedicines, can administer
52
what other excipients may be added to parenteral prep?
preservatives
- Multi-dose injections: not using whole contents of vial in one go. Must maintain stability
- Generally low concs
- Co-solvents: have some issues but higher concs
antioxidant
buffers: acidifying/alkalinising agents for pH control
Tonicity adjustment
53
examples of preservatives and concs used in paenteral?
```
Benzalkonium chloride 0.01
Benzoid acid 0.17
Benzyl alcohol 1-2
Chlorobutanol 0.1-0.5
Chlorocresol 0.1
Cresol 0.15-0.3
Ethanol >10 % v/v
Glycerol 10-20 % v/v
Propylene glycol 15-30 % v/v
```
54
examples Antioxidants excipients used in parenteral administration
- Nitrogen gas Oxygen displacement Used to fill the headspace
- Ascorbic acid (vitamin C) 0.01-0.1
- Alpha-Tocopherol (vitamin E) 0.001-0.05
- Butylated hydroxyanisole (BHA) 0.03 (IM)
- Butylated hydroxytoluene (BHT) 0.0002-0.002 (IV)
- Sodium metabisulphite (acid) 0.01-0.1
55
what antioxidant excipient is also used as pH adjustment?
Ascorbic acid (vitamin C) 0.01-0.1%w/v
56
Antioxidant activity potentiated by what agents? 2 examples
chelating agents
• Citric acid 0.3-2.0%
• EDTA 0.0005-0.01 %
57
how is pH controlled and in what range?
Ideal pH ca. 7.4
| Acceptable range: 3.0-9.0
58
2 examples of Acidifying agents?
HCl
| Sulfuric acid
59
3 examples of Alkalinising agents?
Sodium bicarbonate
Sodium citrate
Sodium hydroxide
60
what may cause pH changes?
* Interaction with container
| * Changes in storage conditions
61
6 examples of buffers used (excipients)?
* Citric acid
* Sodium citrate
* Sodium acetate
* Sodium lactate
* Monobasic sodium phosphate
* Dibasic sodium phosphate
62
tonicity reminder, define:
• Isotonic
• Hypotonic
• Hypertonic
* Isotonic (osmotic pressure = plasma)
* Hypotonic (osmotic pressure < plasma)
* Hypertonic (osmotic pressure > plasma)
63
what 2 excipients may be used to adjust tonicity?
* Sodium chloride
| * Dextrose
64
what is Blood osmolality value range?
Blood osmolality 280-295 mmol/kg
65
antioxidants: how is N gas used?
N gas bubbled into preparation to replace oxygen and lower risk of oxidation OR if have vial/ampoule, use N gas to fill headspace, limit oxidation as preparation in low O2 environment
66
antioxidants: which one used for aq preps and which for oily preps?
why are they good
* For aqueous: ascorbic acid/ Vitamin C
* For oily: Vitamin E.
Good, work at low temps.
67
3 Categories of parenteral preparations
Injections and infusions
o Concentrates for injections or infusions
o Powders for injections or infusions
Gels for injections
Implants
68
Injections and infusions- why useful?
| and types?
Ready to inject or infuse- no preparation req
single dose (pre-filled syringes, ampoules) or multi-dose (vials) containers
69
what are infusions?
Aqueous solutions/ emulsions. Intravenous usually- follow same restrictions
70
restrictions/ rules of infusions?
* Isotonic to blood
* Large volume parenterals (LVP): 100-1000mL, No antimicrobial preservatives
* Sterile solutions: Clear and free of particulates
* Sterile emulsions: Aqueous emulsions, No phase separation (cracking/creaming)
71
in infusions, antimicrobial preservatives should NOT be used when?
```
if:
Single dose is > 15 mL
Route of administration is:
• Intracisternal (in subarachnoid cisternae- CSF of brain ventricules)
• Epidural
• Intrathecal
• ...to the CSF
• Intra-ocular
• Retro-ocular
```
72
what are pharm. Injections ?
Sterile solutions: clear and almost fully particle free. (esp for IV- risk of embolism, avoid)
73
4 examples of pharm injections?
* Insulin solution
* Fluid replacement
* Antibiotics (e.g metronidazole)
* Blood-related products
74
injections & infusions are...
Sterile emulsions:
• No phase separation: cracking/ creaming- reversible but avoid
• < 3 microM
75
injections & infusions 3 examples and uses
• Diazemuls®- diazepam in o/w emulsion
Sedation. Premedication for general anaesthesia
Muscle spasms/convulsions
Control of anxiety/agitation in delirium tremens
• Propofol (Diprivan®)
General anaesthesia
• Parenteral/total parenteral nutrition
Essential fatty acids
Used in drug formulation
76
sterile suspensions- 3 facts
| (compaction, RoA, which is preferred RoA)?
* No caking- compact sediment, hard to go back into suspension
* SC or IM (coarse suspensions)
* IV possible (colloidal suspensions)100nm approx.. small particles, avoid embolism risk
77
hows Powder for injection/suspension given/ used?
* To be reconstituted
* Suitable vehicle- Vehicle for reconstitution must be compatible- avoid accidental caking.
* Importance of particle size
78
what do injection or infusions require?
additional handling prior to administration
• Powder for injection
Sterile solids forming a solution or suspension after reconstitution
Usually lyophilised- need to add a suitable sterile vehicle
• Powder for concentrate for solution for injection/infusion
Need to add a suitable vehicle, then need to dilute prior to administration
• Concentrate for solution for injection/infusion
Need to dilute prior to administration
79
injection or infusion recon ... what to follow?
* Instructions provided on how to reconstitute and/or dilute- must follow carefully
* Final product must meet requirements for injections/infusions
80
Gels for injections
i.e. viscous solutions
can be?(2)
-Sterile semi-solid preparation
```
-Modified release
Somatuline Autogel®
Acromegaly
Gastroenteropancreatic neuroendocrine tumours
Neuroendocrine tumours
```
81
how are Gels for injections administered?
| what can patients be trained on?
Deep SC (no fold of skin prior to injection)prefilled syringe. Patients can be trained on how to self inject
82
3. implants RoA?
SC or IM usually
83
implants types + what dot hey consist of?
Pellets/Rods
Sterile
Drug +/- excipients- depends on properties
Biodegradable or not think about how to remove- surgical process
84
of rod implant?
ZoladexTM implant- biodegradable
• Goserelin
LHRH analogue (nonapeptide)
Prevents testosterone/oestrogen production
Hormone sensitive prostate/breast cancers
Endometriosis/endometrial thinning
Uterine fibroids
Assisted reproduction: preparation for superovulation
• Biodegradable polymer matrix
• Rod 1.5 x 18 mm q28 days
85
example of rod implant?
ZoladexTM implant- biodegradable
• Goserelin
LHRH analogue (nonapeptide)
Prevents testosterone/oestrogen production
Hormone sensitive prostate/breast cancers
Endometriosis/endometrial thinning
Uterine fibroids
Assisted reproduction: preparation for superovulation
• Biodegradable polymer matrix
• Rod 1.5 x 18 mm q28 days
86
example of comtraceptive implant?
```
Nexplanon
• Contraceptive implant, non-biodegradable
• Subdermal (radio-opaque)
• Non-biodegradable polymer
• Progestagen (etonogestrel) only
• 3 years then surg. removed
```
87
example of ocular implant?
```
Oxurdex®
• Intravitreal (ocular)
• Dexamethasone
• Macular oedema/ inflammation (uveitis)
• Administered by ophthalmologist
• Slowly release drug over period of time
```
88
example of implant for brain cancer?
```
GliadelTM wafer
• Local delivery of carmustine
• Glioblastoma- brain cancer. Anti cancer agent
• Biodegradable polymer
• Surgeon administered
```
89
what are implants: resevoirs?
| hows drug stored and released?
* Drug encapsulated within metal/plastic or non-biodegradable polymer
* Drug in solution/dispersed in co-polymer inside reservoir
* Drug released by osmotic pressure
90
how are resevoirs (implants) put in and taken out?
* Special injection device or surgical installation
| * Require removal (usually surgical)
91
Parenteral preparation need to be sterile and what do they have limits on?
particulates and endotoxins
92
main routes of parenteral admin?
IV, IM and SC
o Volumes site of injection and types of formulations will vary
o Advantages and disadvantages may vary depending on the route
o Only nanosuspensions injected intravenously (more in SoM 3)
o Oily preparations can only be injected SC or IM
Can help to prolong release and decrease the frequency of administration
93
What type of prep used for parenteral admin?
Solutions, suspensions and emulsions
| o Some of the formulation consideration will be similar to oral liquid dosage forms
94
PK of parenterals
Pharmacokinetics involves what processes
A = absorption, D = distribution, M = metabolism, E = elimination
95
What processes out of ADME give the information on the elimination of a drug?
metabolism + elimination
96
With pharmacokinetics, we're looking at the change in _ as a function of _
change in plasma concentration as a function of time
97
ADME conc/time: can be ....
+ (appearance: absorption) drug leaves dosage form to get to site of action. Often blood circulation OR
- (disappearance: elimination also distribution) decline in conc. For degradation
98
How can we write the change in plasma concentration/ time using d notation?
dC/dt
99
What is the change in plasma concentration as a function of time equal to for a drug following zero-order kinetics?
dC/dt = k
100
What is the change in plasma concentration as a function of time equal to for a drug following first-order kinetics?
dC/dt = kC
101
What is the change in plasma concentration as a function of time equal to for a drug following second-order kinetics?
dC/dt = kC²
102
typical plasma-concentration time graph. Include labels for: the axes, Cmax, tmax, MEC, MTC/MSC, the therapeutic window, the distribution phase, the absorption phase and on the y-axis the no effect, effect/potency, and toxic.
yellow diagram....
103
What does MSC stand for?
maximum safe concentration
104
What does MEC stand for?
minimum effective concentration
105
During the distribution phase, where is the drug going?
drug is leaving the blood and entering the body tissues
106
During the elimination phase, where is the drug going?
the drug is leaving the body
107
What does the area under the plasma-concentration curve tell us? AUC
the total exposure of the drug
108
What is the bioavailability of IV administration? Why?
100% - drug goes directly to the systemic circulation
109
What is IV bolus administration?
a single intravenous injection
110
why does IV admin not undergo first pass metab?
as direct to blood conc - no absorption phase
111
What is known about IV bolus administration?
the initial dose C0
112
IV bolus administration provides data only on...
the distribution and elimination of a drug
113
How many compartments does IV bolus administration involve? so what does this mean
only one - the body (distribution is negigible)
114
What phase is not present on a plasma-concentration curve for IV bolus administration that is present normally?
the absorption phase (straight to elimination)
| just slope down
115
What does the initial concentration of an IV bolus injection depend on?
- the initial dose
| - the volume of distribution of the drug
116
Why does Vd affect the initial conc of an IV bolus injection? (hint: think of what concentration is normally)
- conc normally mass/volume
- Vd = amount of volume the drug will distribute itself to (includes plasma and fatty tissue)
- therefore conc can be written as C = D/Vd
117
What are the units for volume of distribution (Vd)?
Litres
118
What types of properties of the drug can influence its volume of distribution? Why?
the physico-chemical properties:
- lipophilicity
- plasma protein-binding
these both affect how easy it is for the drug to leave the blood circ + DISTRIBUTE to other tissues
119
What can Vd be used to estimate?
the plasma concentration/loading dose needed
120
If the volume of distribution for a given drug is LARGE, what pharmacokinetic process (A/D/M/E) is important and why?
- distribution
| - there's a high extravascular concentration as drug has left to go elsewhere in body
121
With a high volume of distribution, how are the plasma concentration and half-life affected?
- plasma concentration is decreased
- half-life is increased
↑ Vd = ↑ t1/2
122
Why (how) does volume of distribution affect half-life?
if the drug has left the blood (systemic circ), will take longer for the concentration to halve (and complete elimination)
123
For the average 60kg patient, what is their plasma volume?
3.0L
124
What does a high drug plasma level say about the volume of distribution and why?
- low Vd
Smaller theoretical amount of plasma to achieve that high concentration
- most of the drug has remained in blood rather than distributing to other tissues
125
How do plasma proteins affect the volume of distribution of a drug? (increase or decrease and why)
- decrease
- by binding to drug, they preventing the drug from leaving the circulation and distributing to other tissues
Reason: 99% plasma protein (albumin) bound = restricts distribution
126
How do plasma proteins affect the ability of a drug to have its physiological effect?
- they decrease it
- by binding to a drug, it cannot have its physiological effect
- therefore only unbound drug can have its physiological effect
127
For elimination kinetics, what order do most drugs follow?
first
128
What symbol is used to represent the rate constant, k?
λ
129
Concentration in the plasma= low , Vd =?
| and give drug example
high Vd
(Large theoretical amount of plasma to achieve the low plasma concentration)
Chloroquine Vd = 9000L-purely theoretical (for a 60 Kg adult)
Highly lipophilic partitions into fat
130
how does increased dose affect conc?
Conc = quantity(dose)/volume (Vd)
| Increased C with increased dose
131
What is the equation for an elimination plasma-concentration time curve (e version) for first-order elimination kinetics?
C = C0e⁻^(kt)
132
What is the equation for an elimination plasma-concentration time curve (ln version) for first-order elimination kinetics?
lnC = lnC0 - kt
133
What is the equation for an elimination plasma-concentration time curve (log version) for first-order elimination kinetics?
logC = logC0 - λt/2.303
134
What type of scale can we use to plot the plasma concentration curve and why is it useful?
- semi-log paper
| - easier to read and plot as x-axis is on linear scale
135
How do we convert from ln to log?
ln(x) = 2.303 log(x)
136
inc clearance affect on elim and plasma conc?
| what about half life?
= faster rate of elimination = faster decline in plasma concentration Cl proportional to kEl (elimexcretionsunchanged in urine Plus metabolism (liver) Directly prop
inc clearance = shorter half-life. Inversely prop
137
What is the definition of clearance?
the volume of blood of drug eliminated from the body per hour
138
What are the units for clearance?
L/hr
139
How does a faster clearance affect the rate of elimination and plasma concentration?
increases the rate of elimination and increases the rate of decline of plasma concentration
140
How does a faster clearance affect the half-life?
decreases the half-life
141
What relationship of proportionality does the clearance have to the elimination rate constant?
clearance ∝ k
| directly proportional
142
What relationship of proportionality does the clearance have with the half-life?
clearance ∝ 1/t1/2
| inversely proportional
143
What clearances make up the total clearance?
total clearance = hepatic clearance + renal clearance + other clearance (e.g. lungs, sweat, etc.)
Kcl = Kr + Km
(rate constant for exc) + (rate constant for metabolism)
144
What is the formula for total clearance?
total clearance = k x Vd
145
What is the formula for half-life involving the elimination rate constant?
t1/2 = ln2/k
146
increaseing clearance affect on half life?
shorter.
indirectly proportional
Cl -- 1/ t1/2
147
what does Kel = for first order?
time ^-1
148
Combine the equations for the half-life of elimination and the total clearance. What does it show about the relationship between the two?
- inversely proportional
- if total clearance increases, half-life decreases
- if total clearance decreases, half-life increases
t1/2 = ln2 x Vd / Clt
149
For a drug administered via IV bolus injection, the dose is 500mg, the Vd is 50L, the total clearance is 2L/hr and the MEC is 2mg/L. What is the initial plasma concentration?
C0 = D/Vd
= 500mg/ 50L
= 10mg/L
150
For a drug administered via IV bolus injection, the dose is 500mg, the Vd is 50L, the total clearance is 2L/hr and the MEC is 2mg/L. What is the half-life?
t1/2 = ln2/ k
= ln 2 x Vd / ClT !!
ln2 x 50L / 2L/h
= 17.3h
151
For a drug administered via IV bolus injection, the dose is 500mg, the Vd is 50L, the total clearance is 2L/hr and the MEC is 2mg/L. How many half-lives will it take for the drug to be eliminated from the body?
4-5, considered eliminated when 95-97% has left body
1 t1/2 = 50% C0
2 t1/2 = 25% C0
3 t1/2 = 12.5% C0
[4 t1/2 = 6.25% C0
5 t1/2 = 3.125% C0]
95-97%
152
For a drug administered via IV bolus injection, the dose is 500mg, the Vd is 50L, the total clearance is 2L/hr and the MEC is 2mg/L. How long will it take for the plasma concentration to fall below the MEC?
40.2 hrs
check p132!!!
153
What order does the elimination of multiple IV bolus injections follow?
first-order
154
How many compartments form the compartment system of multiple IV bolus injections?
one compartment system
| system (distribution phase is negligible) so curve mostly tells about elimination
155
Draw the plasma concentration graph for a multiple IV bolus injection where the dose exceeds the MSC. Label the MSC, MEC and therapeutic window.
p134 first pic
156
What is the desired level of drug plasma concentration we want to achieve with multiple IV bolus injections?
steady state (Css)
157
Sketch the plasma concentration graph for multiple IV bolus injections as it approaches steady state. Label the steady state, and axes.
p134
158
What can you do to keep the plasma concentration within the therapeutic window (with multiple)?
* Change dose- lower
| * Change dosing interval- when given and how often (dose distribution)
159
What is the definition of the steady state of multiple IV bolus injections?
the concentration at which the drug entry is equal to the drug exit - equilibrium
160
What is the equation for the steady state of multiple IV bolus injections?
Css = Dose / total clearance x dosing interval (τ)
• Css is the steady state average concentration
161
What can we do to achieve steady state for drugs with a low dose (i.e. takes too long for drug to reach MEC)?
use a loading dose as it will achieve the steady state concentration immediately
162
What is the equation for loading dose?
LD = Css x Vd
163
what does Css = dose/ Clt x dosing interval t
| take into account?
that drug may not be completely excreted before next/couple doses administered.
164
why is larger therapeutic window good for Css?
first dose (when getting up to Css) will more liekly be within range
165
reason to give LD?
get into therap range straight away, to get to Css
| Get response and effective treatment quickly- for seizures etc or cardiac disease
166
Vancomycin is administered IV and has a narrow therapeutic window. Otoxicity has been associated w serum drug levels of 80-100mg/L, but not seen when below 30mg/L. 90% of injected dose excreted via glomerular filtration, the Vd = 35L, the t1/2 = 6 hrs. For repeated administration, trough concentrations prior to next dose should be 5-10mg/L. Initial dose given is 1g. Calculate the total clearance.
ClT = Kel x Vd
t1/2 = ln2 X Vd / ClT
4.04L/hr
167
Vancomycin is administered IV and has a narrow therapeutic window. Otoxicity has been associated w serum drug levels of 80-100mg/L, but not seen when below 30mg/L. 90% of injected dose excreted via glomerular filtration, the Vd = 35L, the t1/2 = 6 hrs. For repeated administration, trough concentrations prior to next dose should be 5-10mg/L. Initial dose given is 1g. How many hours after the 1st dose should the next dose be administered?
C0 = 1000/35
C = 5-10mg/L
k = ln2/t1/2
use lnC = lnC0 - kt
= 9.12hrs?
168
• After multiple administrations, the plasma concentration ....
increases steadily
169
what is Css?
After a while, we reach steady state, at which point the plasma concentration will remain constant
170
loading dose is NOT always required, it depends on what?
drug/clinical indication and on the plasma concentration achieved at a normal dose
further adjustments to subsequent doses (i.e. change to the maintenance dose) may be required if a loading dose is used
171
What is the difference between an IV bolus injection and infusion in terms of the rate of concentration increase?
for a continuous infusion, the rate of concentration increase is more gradual
172
What is the main difference in the way IV bolus injections and infusions are administered?
infusions are administered continuously (constant rate),
| elimination only begins once the infusion is stopped
173
IV or IM: know rate of infusiom?
IV.
| still both admin directly into circulation though
174
Speed of conc increase depends on what for IV infusion?
infusion rate.
Fast= sharp increase
Peak= when infusion stops- nomore drug put in
175
What order of kinetics do IV infusions follow?
first
176
Sketch the concentration time graph for an IV continuous infusion. Label the steady state on the y-axis, and the wash-in, steady-state, and wash-out period on top of the graph.
pic of p 137
177
Wash in stage: influenced by ?
rate of infusion and how long infusion lasts.
178
describe the Css stage on the graph
plateau. infusion stopped, drug coming in and out is the same
179
What issue is encountered in terms of dosage for both multiple IV bolus injections and continuous IV infusions? How is it resolved?
- both take a while to reach steady-state concentration (wash in stage)
- can use a loading dose in both instances or increase infusion rate briefly until Css reached then slow down rate
180
What does the concentration time graph have for IM/SC injections that IV bolus injections/infusions don't? Why?
- an absorption phase
| - the drug needs to leave the dosage form and enter the systemic circulation
181
Put the following dosage forms in order of decreasing rate to onset of action: aqueous suspension, oil-based suspension, aqueous solution, oil-based solution.
- aqueous solution
- aqueous suspension
- oil-based solution
- oil-based suspension
182
If want to change plasma conc, generally have to change (2)?
infusion rate OR duration of infusion
183
plasma conc at steady state = Css. this is reached when t= ?
infinity
| eqm drug in = out
184
Clinical significance of t=t infinity. time takes to reach Css?
• Drug with long half-life: may take days to reach steady state
• Drug with short half-life: Css may be reached in hours
- Consider if loading dose useful. If takes long time to reach CSS: consider LD.
185
similarity in continuous infusion and multiple bolus?
• Same build up, then reach steady state.
186
Continuous or multiple bolus injectyions better to give in clinic?
Continuous...
else Dosing interval got wrong- dotted line have to wait until 3rd dose for MEC.
• Infusion- don’t have to wait with start and reaching effect.
• Loading dose possible
• Want to reach steady state conc ASAP
187
options for clinical use: continuous/ multiple bolus injections?
LD: high conc initially but then reach desired conc asap. Different options on how to give:
• Give IV bolus injection then start with infusion. higher initial conc then over time reach Css.
• Or have infusion at higher infusion rate= in therapeutic window faster but then MUST readjust rate to stay in window for whole time. Must keep track of rate and slow down infusion once Css reached.
o May have issues with toxicity if not adjusted
188
what to presc if need to get to Css quickly e.g. w antibiotics?
LD + infusion
equation w orange arrow !! p 139
Use this equation when calculating conc of drug in plasma at given time when have LD + IV bolus + infusion
Changing rate NOT = reach Css faster, BUT can get to higher levels.
189
changing rate of infusion affect on Css time to get there?
Changing rate NOT = reach Css faster, BUT can get to higher levels.
Infusion rate changed at ONE HALF-LIFE
• Short half life: have less time to switch infusion rate. Long: have more time
190
Why haloperidol not given IV? (Not oily- not IV anyway)
• Clinically: Haloperidol is not given iv for clinical reasons it can cause serious cardiac dysrhythmias if given iv.
• Formulation: look at the two formulations and at your lecture notes. Apart from the side effects mentioned, what else explains why IM
administration is preferred for haloperidol decanoate?
